Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
Front Immunol. 2024 Aug 29;15:1445711. doi: 10.3389/fimmu.2024.1445711. eCollection 2024.
Patients with pathogenic variants in the GATA Binding Protein 2 (), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males.
A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with haploinsufficiency followed at the National Institutes of Health. Student's -test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations.
Of 68 patients with haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males.
Females with haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.
GATA 结合蛋白 2 （）的致病性变异会使造血转录因子失活，导致患者在低于预期年龄时罹患人乳头瘤病毒（HPV）相关的肛门生殖器癌。本研究通过两位妇科医生对具有杂合性缺失的女性队列进行系统评估，以明确 HPV 肛门生殖器疾病的严重程度和范围，并与男性患者进行比较。
对在国立卫生研究院接受治疗的杂合性缺失患者进行了 17 年的病历回顾性分析，包括实验室、组织病理学和细胞病理学记录。采用 Student's -test 和 Mann-Whitney U 检验或 Fisher's 确切检验比较连续或分类变量之间的差异，Spearman's rho 系数用于分析相关性。
在 68 例杂合性缺失患者中，27 例（40%）以 HPV 疾病为首发表现。女性 HPV 发病中位年龄为 18.9 岁（15.2-26.2），男性为 25.6 岁（23.4-26.9）。52 例（76%），27 例女性和 25 例男性，发展为 HPV 相关的鳞状上皮内病变（SIL），包括 2 例男性发生口腔癌。21 例患者发生肛门生殖器高级别 SIL（HSIL）或癌（16 例女性与 5 例男性，分别为 59%与 20%，p=0.005），女性中位发病年龄为 27 岁（18.6-59.3），男性为 33 岁（16.5-40.1）。女性比男性更需要进行 >2 次手术以治疗复发性 HSIL（p=0.0009）。在 30 例行造血干细胞移植（HSCT）以治疗因杂合性缺失引起的疾病的患者中，12 例（9 例女性，3 例男性）持续存在 HSIL/HPV 疾病。其中 9 例女性中有 8 例行围手术期 HSIL 治疗。7 例患者中有 5 例在 HSCT 后接受了 HPV 疫苗接种，并且在 HSCT 后 2 年没有或仅有轻微的 HPV 疾病证据。2 例接受免疫抑制治疗的患者 HPV 疾病持续存在。3 例男性患者的 HPV 疾病/低级别 SIL（LSIL）均已消退。
杂合性缺失的女性表现出复发性、多灶性肛门生殖器 HSIL 的风险增加，需要频繁监测和多次治疗。对于广泛、多灶性生殖器 HSIL 对多次手术无反应的女性，应考虑杂合性缺失。这类人群可能受益于 HSCT 等早期干预措施，并接受妇科肿瘤医生和妇科医生的持续强化监测和治疗，以治疗 HPV 肛门生殖器疾病。
